The two mouse lines C57BL/6J and BALB/cByJ, which have a different genetic basis, exhibit behavioural differences, particularly in the tests considered to explore anxiety and response to stress (such as exploratory behaviour in a stressful situation). Broadly speaking, BALB/cByJ mice are considered to be "anxious", unlike C57BL/6J mice. Functional differences in certain GABAergic neurotransmission systems might be involved in these behavioural differences. Type A GABA receptors, or GABA(A) receptors, are pentamers formed from combinations of 2 alpha subunits from among 6 different a proteins, 2 beta subunits from among 3 different 0 proteins, and a fifth subunit from among 3 possible 7 proteins, 3 possible p proteins, or 8, F, 0 and 71 proteins. There are therefore a number of receptor variants, the three most common forms being 2 alpha(1)/2 beta(2)/gamma(2), 2 alpha(2)/2 beta(3)/gamma(2). and 2 alpha(3)/2 beta(3)/gamma(2). These mice also exhibit differences in response to etifoxine in some stress tests. As etifoxine binds particularly to the beta-2 (Gabrb(2)) subunits of the GABAA receptors, we therefore analysed the expression of this protein and its messenger RNA (mRNA) in the brain of these two adult mouse lines first of all. We observed that in the BALB/cByJ mouse, and in the absence of any treatment, the expression of Gabrb2 is constitutively and specifically increased in the dentate gyrus, the CA3 region of the hippocampus and the anterodorsal thalamus, which are structures of the Papez circuit. This overexpression affects both mRNA and proteins and means that the subunit composition of the GABAA receptors there is different. There might be a relationship between this difference and the behavioural differences of these mice. In fact, the Papez circuit, which joins the archeocortex forming the hippocampus via the anterior thalamus and other structures to the parietal and frontal limbic neocortex, is considered to be the major circuit involved in processing emotional information, particularly anxiety. The Gabrb2 protein, the target of etifoxine, might therefore be particularly involved in regulating responses to stress and anxiety. Subsequently, we analysed the effect of acute treatment with etifoxine after 30 minutes, 4, 8 and 12 hours on the expression of Gabrb2 mRNA in BALB/cByJ mice. No difference of expression was observed. This result shows that the point of impact or the target of etifoxine is the constitutive beta 2 protein of the GABAA receptor and not its transcript (mRNA). This result is compatible with the tack of tolerance effect (habituation) or rebound effect with this treatment observed in preclinical and clinical studies. These results therefore establish a possible [ink between one of the proteins on which etifoxine acts directly and stress response and anxiety behaviours, but also between the lack of induction of any variation in the expression of the gene of this protein by etifoxine and the tack of tolerance effect (habituation) and rebound effect of this treatment. This last point merits more detailed investigation in further studies.
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